Persons living with HIV (PLHIV) have a higher risk of cardiometabolic risk factors and concomitantly, are at higher risk of adverse cardiovascular disease (CVD) events than individuals not infected with HIV. Unfortunately, the biological mechanisms underlying the pro-atherogenic state in HIV-infection are incompletely characterized. In our own work, we have successfully employed an integrated multi-omic systems biology approach in human cardiovascular cohorts to identify novel biomarkers and mechanisms of disease pathogenesis that are experimentally validated, including a signature of endoplasmic reticulum (ER) stress. Thus, using integrated 'omic profiling in two unique biorepositories of PLHIV coupled with experimental validation in cell-based models, we propose to test the hypothesis that ER stress is involved in the pathogenesis of CVD in PLHIV, and to identify novel mechanisms of CVD in PLHIV. Our specific aims are: (1) To test the hypothesis that genetic and metabolomic markers reporting on endoplasmic reticulum (ER) stress are associated with CVD in PLHIV. In this Aim, we will perform candidate gene genotyping and targeted metabolomic profiling on two cohorts of PLHIV using a nested case-control design of cases suffering incident CVD events and 2:1 matched controls (N=555 PLHIV selected from the Center for Aids Research [CFAR] Network of Integrated Clinical Systems [CNICS] and N=339 PLHIV selected from the Duke HIV Database); (2) Using a systems biology integrated 'omics approach, to identify novel biomarkers and/or pathways associated with cardiovascular disease outcomes in PLHIV. In this Aim, we will integrate GWAS (data available through CNICS), whole genome methylation, targeted microRNA and metabolomics in a nested 1:1 CVD case-control cohort and using a pathways-based approach, identify potential novel mechanisms of CVD pathogenesis in PLHIV; and (3) Using cultured cell lines to test the hypothesis that primary HIV infection induces changes in ER stress markers, to assess for change in novel metabolites identified in Aim 2 with HIV infection, and to differentiate molecular signatures of primary HIV infection from those of antiretroviral therapy through drug exposure studies.